chr12-100536917-T-A

Variant names:

• chr12-100536917-T-A
• rs7138843
• NM_001206979.2:c.832-31T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001206979.2(NR1H4):​c.832-31T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,248,466 control chromosomes in the GnomAD database, including 14,355 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (4948 hom., cov: 33)
  • Exomes 𝑓: 0.062 (9407 hom.)
• Consequence: NR1H4 NM_001206979.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.106
• Publications: 9 publications found

Genes affected

NR1H4 (HGNC:7967): (nuclear receptor subfamily 1 group H member 4) This gene encodes a ligand-activated transcription factor that shares structural features in common with nuclear hormone receptor family members. This protein functions as a receptor for bile acids, and when bound to bile acids, binds to DNA and regulates the expression of genes involved in bile acid synthesis and transport. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Feb 2016]

NR1H4 Gene-Disease associations (from GenCC):

• cholestasis, progressive familial intrahepatic, 5

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-100536917-T-A is Benign according to our data. Variant chr12-100536917-T-A is described in ClinVar as Benign. ClinVar VariationId is 1246288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR1H4	NM_001206979.2	c.832-31T>A		intron_variant	Intron 7 of 10	ENST00000392986.8	NP_001193908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR1H4	ENST00000392986.8	c.832-31T>A		intron_variant	Intron 7 of 10	1	NM_001206979.2	ENSP00000376712.3

Frequencies

GnomAD3 genomes AF: 0.171 AC: 26043 AN: 151978 Hom.: 4917 Cov.: 33

Gnomad AFR AF: 0.445

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.0423

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0195

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.117 AC: 25714 AN: 219168 AF XY: 0.107

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.171

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.0459

Gnomad NFE exome AF: 0.0204

Gnomad OTH exome AF: 0.0798

GnomAD4 exome AF: 0.0617 AC: 67609 AN: 1096370 Hom.: 9407 Cov.: 15 AF XY: 0.0621 AC XY: 34851 AN XY: 560980

African (AFR) AF: 0.463 AC: 11422 AN: 24694

American (AMR) AF: 0.164 AC: 5632 AN: 34304

Ashkenazi Jewish (ASJ) AF: 0.0655 AC: 1476 AN: 22524

East Asian (EAS) AF: 0.494 AC: 18643 AN: 37710

South Asian (SAS) AF: 0.139 AC: 9878 AN: 71218

European-Finnish (FIN) AF: 0.0448 AC: 2325 AN: 51944

Middle Eastern (MID) AF: 0.0620 AC: 252 AN: 4066

European-Non Finnish (NFE) AF: 0.0171 AC: 13727 AN: 802310

Other (OTH) AF: 0.0894 AC: 4254 AN: 47600

GnomAD4 genome AF: 0.172 AC: 26110 AN: 152096 Hom.: 4948 Cov.: 33 AF XY: 0.173 AC XY: 12898 AN XY: 74346

African (AFR) AF: 0.446 AC: 18486 AN: 41458

American (AMR) AF: 0.142 AC: 2176 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 251 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2342 AN: 5170

South Asian (SAS) AF: 0.160 AC: 772 AN: 4830

European-Finnish (FIN) AF: 0.0423 AC: 448 AN: 10596

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0195 AC: 1324 AN: 67970

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.0908 Hom.: 377

Bravo AF: 0.193

Asia WGS AF: 0.318 AC: 1101 AN: 3466

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 20, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.2
DANN	Benign	0.69
PhyloP100		-0.11
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7138843; hg19: chr12-100930695;